CaPPtain's Blog

You wait for an aspirin trial to report, then, FOUR arrive at
once. They all have catchy names: ASCEND, ARRIVE, ASPECT and
ASPREE, all with different target populations. There is some
interesting new information about aspirin in the elderly (over 70)
from the ASPREE trial, but I don't think it will have much impact
on CaPP3 ASPECT showed that aspirin (300mg) combined with acid
blockade was good for reducing cancer risk in Barrett's oesophagus,
a chronic effect of acid damage due to reflux from the stomach.
ARRIVE and ASCEND concluded there wasn't much mileage in terms of
preventing cardiovascular events in giving aspirin (100mg) to
people with a moderate risk of such problems or diabetics
respectively. These studies did not address the recent publication
from Peter Rothwell linking the effects of aspirin to bodyweight;
75/100mg aspirin was only effective in preventing vascular events
in patients who weighed less than 70kg. The studies were too short
term to look at cancer chemoprevention in any detail. The most
important information for the CaPP community was from ASPREE, which
stands for Aspirin in Reducing Events in the Elderly. Based on over
19,000 recruits in Australia and the United States, the trial
randomised people aged over 70, to aspirin 100mg aspirin EC or
placebo over 5 years. There were a significant number of adverse
events, which wasn't surprising. Other research has previously
shown that the risk of bleeds rises steeply in old people. The
surprising result was that the risk of dying of cancer actually
increased over the 4.7 years of the study. This fits with an
analysis of aspirin trials and cancer incidence in the elderly,
carried out by Peter Rothwell's team in Oxford, which he spoke
about at the International Aspirin Foundation meeting in Edinburgh
recently.

The idea that older people might not benefit from aspirin cancer
prevention has been a subject of discussion for many years. In the
1990's a string of studies looked at cancer rates in people who had
taken aspirin and noted a significant reduction in cancers. The one
exception was a study by Paganini-Hill and colleagues. Their study
of the Leisure World Cohort looked at people in retirement homes in
California, and through questionnaires, including self-reported
aspirin usage, reported higher cancer rates. Paganini-Hill proposed
that the aspirin self-medication used by the cohort was primarily
low dose to prevent myocardial infarction and that a higher dose
was needed for cancer chemoprevention.

We have two theories about the ASPREE & the Leisure World
Cohort studies, which might be connected.

The first is that we know aspirin can act to reduce the
inflammatory changes around an early cancer. This might provide
improved access for the immune system leading to its destruction.
But, what if the cancer cells have already picked up genetic
changes that mean the immune system cannot "recognise" the cancer?
Removal of the inflammatory response would then make it easier for
the cancer to progress.

A second idea is that, in plants, salicylates, from which
aspirin is made, act as a trigger for programmed cell death. This
energy- dependent process, also known as apoptosis, is used by
plants to kill off faulty cells, usually because of infection. If
triggering apoptosis is part of the way that aspirin works in early
cancers, then it might not work so well in the very old. Research
done over the last 15 years by the Mitochondrial Genetics team in
Newcastle (which involved our own Gill Borthwick when she worked as
a research scientist) showed that the stem cells in the bowel
slowly lose the normal function of their mitochondria. By the age
of 70, about 10% of the stem cells are no longer working properly.
Mitochondria are the energy units inside cells and are critical to
normal functions, including the process of apoptosis.

So we have two overlapping ideas; damping down inflammation
might let any cancers already in the system progress and "old
colons" might not respond as well to the benefits of aspirin in the
same way as they do earlier in life.

All this is based on people from the general population and not
people with Lynch syndrome. There are reasons to think the response
to aspirin might be greater in Lynch syndrome, based on what we
already know. In addition, when the risk of cancer is much higher,
the benefits of, say, a 30% reduction are much greater so the risk
/ benefit ratio is different.

We also need to think about our biological fitness rather than
take age as a number. Over the last century, our life expectancy
has increased for reasons we are still learning about. That means
that an average 70 year old now is biologically younger than a 70
year old in the last generation. Putting together the evidence now
emerging, we need to be alert to a slight increase in cancers when
people start taking aspirin later in life. People with Lynch
syndrome are already alert to any unusual symptoms and LS cancers
tend to be less able to spread to the rest of the body, giving time
in most cases for curative treatment. In our European Prospective
LS Database, the risk of dying of cancer is much lower than would
be predicted from similar cancers in the general population. While
the protection against bowel cancer may decline in older people,
there will almost certainly still be benefit and this will show
through once any tumours already "in the system" have been dealt
with.

These latest studies, along with the Rothwell paper earlier in
the year on the effects of different aspirin dosages, have
reinforced the importance of CaPP3 for future generations. CAPP2
demonstrated a reduction with 600mg aspirin, in Lynch syndrome
cancers after 5 years. We need to know the relative benefits of
different doses in people with LS of different shapes, sizes and
ages.

How does this all relate to CaPP3 study participants over the
age of 70? We should emphasise to people around 70 or older who are
thinking of starting the trial that the side effect risk is higher
in older people and that we should be extra vigilant for unusual
symptoms in the early years of the study. For those CaPP3 study
participants over the age of 70 already in CaPP3, regular contact
addressing any adverse events and symptoms should be
maintained.

The CaPP3 study, this week, in the UK has now reached 1405
patients (total with international 1658). The UK recruitment target
is 1500. Thank you to all the recruiting centres both national and
international I think it is reasonable to use that phrase now
popular with poster makers in the UK, "keep calm and carry on."

In July 2018, the Lancet published an important article about
the health benefits of aspirin by an international team led by
Peter Rothwell of Oxford. It contained important new information
yet it received little media attention. The reason, I think, was
that it was complicated. The authors noted that the benefits of
long term aspirin in prevention of heart attacks and strokes were
not as great as some early work would have suggested and they set
out to investigate the effects of dose, age and gender. The idea is
that we can use these combined historical data to estimate the best
dose for a person of a particular size, age and gender. The general
accepted wisdom is that even a little aspirin is enough to
permanently inactivate platelets, even though the drug is broken
down as soon as it reaches the liver in the circulation from the
gut. A reanalysis of more than 117,000 people who took part in 10
clinical trials revealed a complicated story. The low dose now
commonly used of between 75 and 100mg per day was only effective in
smaller people and was not protective in larger or heavier people.
This seemed to be an effect of body size rather than a result of
being simply overweight as it was found to relate to height as well
as weight. Using a full size aspirin tablet of 325mg or more
reversed the effect; there was a protective effect among people
over 70kg (11st) whereas the smaller people, more often female, did
worse on the bigger doses than the control group, that is that
cardiovascular events were slightly more common among aspirin
takers than among people not taking aspirin. The take home message
was that the cardiovascular benefits of aspirin are dose dependent
but that you can have too much of a good thing. Spreading a larger
dose over a twice daily dose seemed to be beneficial.

The second part of the study looked at cancer rates in the five
trials where this was possible (we must remember that these trials
did not involve people with Lynch Syndrome, more about this later).
Again, there was evidence of a dose effect. First, they looked at
the 20 year influence on colorectal cancer. The 75-100mg dose was
protective against colorectal cancer only in those who were under
70kg whereas the 325mg group saw protection up to 80kg also.

This fits with our report in 2015 that the risk of cancer was
increased in the CAPP2 study in people who were overweight and that
this effect was reduced by those who were in the 600mg aspirin
treatment group.

Finally, they looked at the short-term cancer rates and found
that there was no overall short term effect on either incidence or
mortality. Rumour has it the Oxford team will be publishing a more
detailed analysis of the cancer data.

What does this all mean for CaPP3? First, it reinforces the case
for our trial. Clearly there is still much to learn about the
optimal dose of aspirin. CaPP3 will help target the groups who will
benefit most and identify the best dose. As I mentioned above, the
trials included in this analysis consisted of a random set of the
general population, whose lifetime risk of bowel cancer is much
less than for a person with Lynch Syndrome. The effects on
cardiovascular risks are relatively small so there are no major
ethical concerns for people in the target group for CaPP3
recruitment, namely adults with Lynch Syndrome. In absolute terms,
the effects of body size and age are relatively small, which is why
they have taken so long to be discussed, so we should not change
the design of CaPP3 at this late stage when we are close to the end
of recruitment. The case for the CaPP3 trial continuing is
increased as we need to know more about how to choose the right
dose and duration.